Project 3 of the program application will test polyamine biosynthesis inhibitors (PBIs) for the treatment of[unreadable] HlV-associated dementia (HAD) based on the hypothesis that macrophage activation is central to the[unreadable] pathogenesis of this disease process. This project will be housed within the Hawaii AIDS Clinical Research[unreadable] Program (HACRP, PI: Cecilia Shikuma) University of Hawaii John A. Burns School of Medicine, and will be[unreadable] performed in close collaboration with the central core laboratory at Pathologica (Project 1, Cores B and C)[unreadable] and with the simian PBI trials conducted at Harvard (Project 2). Project 3 will utilize banked specimens from[unreadable] our NINDS-funded Hawaii Aging with HIV Cohort (HAHC) and generate data in vitro testing whether HIV-infected[unreadable] activated M/MOs from HAD patients are preferentially killed by PBIs. In tandem, we will identify[unreadable] patients with HIV cognitive impairment in real-time using an abridged combination of neuropsychological[unreadable] tests (NPZ-4) shown to correlate highly with the diagnosis of HAD in our patients. In these patients, we will[unreadable] define the unique blood M/MO gene and protein expression pattern ("ProMac Profile") associated with[unreadable] neurocognitive dysfunction. Finally, working closely with our collaborators, NIMH and the FDA, we propose[unreadable] to recruit subjects with HAD from HAHC participants who performed poorly on NPZ-4 testing, and launch, in[unreadable] the later half of the second year of funding, a phase 1 clinical trial of a PBI drug targeting HAD.[unreadable] The strengths of this proposal lie in our existing HIV clinical trials infrastructure, our neurocognitively well-characterized[unreadable] patient and banked specimen resources of the Hawaii Aging with HIV Cohort, and the[unreadable] translational research expertise of our team with a track record of close collaboration among the Program[unreadable] investigators. The specific aims as proposed will extend our knowledge of the pathogenesis of HAD and[unreadable] assess the safety and potential efficacy of a class of chemical compounds specifically directed against the[unreadable] likely central mechanism involved in the development of HAD.[unreadable] Specific Aim 1) Utilizing banked specimens, to determine in vitro the killing potential of the selected PBI(s)[unreadable] against activated M/MOs from subjects with HAD; and to assess various factors (HIV DNA, novel activation[unreadable] flow markers) potentially related to its efficacy. Hypothesis to be tested: 1) PBIs will demonstrate effective[unreadable] killing of activated M/MOs from HAD subjects, 2) High HIV DNA within activated M/MOs will correlate to[unreadable] enhanced killing by PBIs, 3)High levels of novel activation flow markers will correlate to enhanced killing by[unreadable] PBIs. Specific Aim 2) To define the "ProMac profile" (blood M/MO gene and protein expression patterns)[unreadable] associated with neurocognitive impairment using fresh specimens captured in real-time within the Hawaii[unreadable] Aging with HIV Cohort, and to evaluate the killing potential of PBIs against M/MOs with this profile.[unreadable] Hypotheses to be tested 1) A unique "ProMac profile" will be found in M/MOs isolated from HIV-infected[unreadable] subjects with neurocognitive dysfunction, 2) M/MOs with this "ProMac profile" will be preferentially killed by[unreadable] PBIs. Specific Aim 3)To conduct Phase 1 clinical trials utilizing a PBI drug in individuals with HAD.[unreadable] Hypothesis to be tested 1) PBIs given to patients with HAD will be safely tolerated and will result in a[unreadable] decrease in biomarker(s) indicative of a persistently activated M/MO phenotype.